Impact of Prior mRNA COVID-19 Vaccination on PFS2 in NSCLC Patients Receiving Second-Line Immune Checkpoint Inhibitors: A Real-World Analysis

Background: Immune checkpoint inhibitors (ICIs) targeting the PD-1 axis represent standard second-line therapy for metastatic non-small cell lung cancer (NSCLC). Emerging data suggest that SARS-CoV-2 mRNA vaccines may enhance antitumor immunity through innate immune activation and type I interferon signaling, potentially sensitizing tumors to PD-1 blockade. The clinical impact of patients initiating second-line nivolumab remains unclear. Methods: In this retrospective single-center cohort study, 88 patients with recurrent stage IV NSCLC who received second-line nivolumab between 1 January 2023 and 1 January 2026 were analyzed. Vaccination exposure was defined using a 6-month pre-treatment window prior to nivolumab initiation (T0). Patients were stratified according to receipt of ≥2 versus 0–1 mRNA COVID-19 vaccine doses within the 6 months preceding T0 (n = 45 and n = 43, respectively). The primary endpoint was progression-free survival from nivolumab initiation (PFS2). Survival outcomes were estimated using the Kaplan–Meier method and evaluated using Cox regression models. Results: With a median follow-up of 22.4 months, median PFS2 for the overall cohort was 11.1 months (95% CI, 9.4–15.1). Patients receiving ≥2 mRNA doses had significantly longer PFS2 than those receiving 0–1 dose (14.0 vs. 9.6 months; p = 0.04). In multivariable analysis, ≥2 doses were independently associated with reduced risk of progression or death (aHR 0.52, 95% CI 0.31–0.88; p = 0.01). Non-adenocarcinoma histology and baseline brain metastasis were independently associated with shorter PFS2. Conclusions: Receipt of ≥2 mRNA vaccine doses within 6 months before nivolumab initiation was independently associated with prolonged PFS2 in metastatic NSCLC. Prospective multicenter validation is warranted.